Isolations of fluconazole resistant Cryptococcus neoformans strains from AIDS patients who have been treated with fluconazole are on the rise. Although the genetic mechanisms of resistance to fluconazole in such isolates have not been elucidated, the isolates are reported to have stable and sharp cut-off points in minimum inhibitory concentrations (MIC). We have studied fluconazole heteroresistant C. neoformans strains from two AIDS patients and one HIV-negative patient. The two AIDS patients, one from Italy and one from the U.S. had been exposed to fluconazole while suffering from cryptococcosis and but the HIV-negative cryptococcosis patient was in Israel who has never been treated with any antimycotic agent. Resistance to fluconazole in these strains lacked cut-off points and the resistance was unstable in the absence of the drug. Purification of sensitive or stable resistant clones was not possible. Evidence showed that resistance in these strains is innate and unrelated to azole exposure and that the patterns of resistance resembled what had been described for methicillin resistance in Staphylococci.